DESCRIPTION: The overall objective of this research proposal is to understand DNA mismatch repair of mammalian cells. The Principal Investigator proposes to define the roles and relationships of four mismatch repair protein homologs, hMSH2, hMLH1, hPMS1, and hPMS2. Also, he plans to identify additional proteins required for mismatch repair. Finally, the Principal Investigator proposes to identify other processes that either cooperate or interact with DNA mismatch repair to help maintain genetic stability. Specific aims will include studying physical interactions among the four human proteins hMLH1, hPMS1, hPMS2, hMSH2 that are likely to be involved in the early steps of DNA mismatch repair. Portions or domains of the proteins which are responsible for protein-protein interactions will be defined. Both in vitro and in vivo approaches will be used. A second specific aim will be to use the yeast "two hybrid" system to isolate new DNA mismatch repair genes. Studies should also identify other processes or pathways that interact with DNA mismatch repair. An attempt will be made to develop antibodies against the hMLH1 and hPMS2 proteins to study their cellular localization. The use of these antibodies in diagnostic studies will also be explored.